The Nuclear Control of Cell Growth and Differentiation (NC) Program is a laboratory-based, basic science program focused on the genetic basis of cancer with collaborative connections to all other programs within Huntsman Cancer Institute. The research goal is to investigate fundamental mechanisms in the nucleus that go awry in the cancer cell that may be exploited to impact new approaches to cancer prevention, diagnostics, prognostics, and treatment. Areas of particular emphasis include maintenance of genome stability, including DNA damage and repair; epigenetic involving DNA methylation and chromatin dynamics; transcripfional regulation of gene expression through sequence-specific DNA binding proteins, including ones implicated in human cancer; and analysis of transcriptional networks that drive embryonic development, organogenesis, and cell metabolism. The NC Program has depth and strength in all major experimental approaches, including basic chemistry and biochemistry; structural biology; molecular, cell, and cancer biology; genetic and genomic approaches; and the use of animal systems for discovery and validation of cancer pathways in humans. Major achievements over the last five years include discovery of a DNA demethylase that directs epigenetic programming and is associated with cancer progression, elucidation of critical downstream targets of oncogenic transcription factors in the ETS family in the context of sarcoma and prostate cancer, and creation of mouse models of sarcoma through pioneering gene targeting technologies. Led by Barbara Graves, PhD, and Stephen Lessnick, MD, PhD, the Program has 23 members from nine departments and two colleges. There are three HHMI Investigators. As of December 2008, NC members had $9.8M in peer-reviewed annual direct costs for research projects, including 11% from NCI. Since July 2003, their research has been reported in 220 publications, of which 9% were intra- and 14% were interprogrammatic collaborations. Six new members are MD/PhDs, including the Co-Leader, and bring a clinical perspective to the Program. More than 90% of members have peer-reviewed funding and several members have highly distinguished awards, including the Nobel Prize in Medicine or Physiology, awarded to Mario Capecchi, PhD, for his pioneering work in gene targeting in 2007. The Cancer Center enhances the research goals and integration of this Program through fostering collaborative and transdisciplinary interactions as well as providing access to shared resources, NC programmatic funds, and support for faculty recruitments. In the next five years, the NC Program will continue initiatives to elucidate basic cancer mechanisms and to educate both Center members, as well as the next generation of cancer researchers, with the ultimate goal of impacting the care of cancer patients within an individualized oncology paradigm.